Novel endothelin receptor antagonist attenuates endotoxin-induced lung injury in sheep

Kuklin, V. N.; Киров, М. Ю.; Evgenov, Oleg V.; Sovershaev, Mikhail A.; Sjöberg, Jonas; Kirova, Svetlana S.; Bjertnæs, Lars J.

doi:10.1097/01.ccm.0000114575.08269.f6

Cited by 46 publications

(68 citation statements)

References 34 publications

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“…It is well established that infusion of LPS stimulates release of inflammatory mediators such as TNF-α, IL-8, and ET-1 (3,21,39). Similarly, ET-1 stimulates monocytes and macrophages to release TNF-α and IL-8 (11,12), and enhanced plasma concentrations of TNF-α, IL-8, and ET-1 were found after 4 h in endotoxemic subjects (19). Finally, increases in ET-1 and TNF-α were found to be consistent in a study that used endothelin receptor antagonist bosentan (41).…”

Section: Animals and Treatmentsmentioning

confidence: 96%

Time-dependent expression of endothelin-1 in lungs and the effects of TNF-α blocking peptide on acute lung injury in an endotoxemic rat model

et al. 2011

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Endothelin (ET)-1 is a potent vasoconstrictor that has been implicated in the pathogenesis of a number of diseases, and some studies suggest that circulating ET-1 is elevated in sepsis. The present study investigated whether ET plays a role in sepsis-mediated acute lung injury and whether its expression could be down regulated by blockade of TNF-α in septic lung. Male Wistar rats at 8 weeks of age were administered with either saline or lipopolysaccharide (LPS) at different time points (1, 3, 6 and 10 h) and various tests were then performed. The features of acute lung injury were observed at 1 h after LPS administration, which gradually became severe with time. Systolic and diastolic pressures were reduced just about one hour after LPS administration, whereas pulmonary TNF-α levels were significantly increased at various time points after LPS administration. LPS induced a time-dependent expression of ET-1 and ET A receptor in the lungs compared to control, peaking and increasing by 3 fold at 6 h after induction of endotoxemia, whereas levels of ET B receptor, which has vasodilating effects, were remarkably down regulated time-dependently. We conclude that time-dependent increase of ET-1 and ET A receptor with the down regulation of ET B receptor may play a role in the pathogenesis of acute lung injury in endotoxemia. Finally, treatment of LPS-administered rats with TNF-α blocking peptide for three hours significantly suppressed levels of pulmonary ET-1. These data taken together, led us to conclude that differential alteration in ET expression and its receptors may be mediated by TNF-α and may, in part, account for the pathogenesis of acute lung injury in endotoxemia.The presence of multiple organ dysfunction syndrome (MODS) is the most important determinant of prognosis in endotoxemia and sepsis (6), and the lung is the most common organ with the most infection, involved in a fatal sepsis that leads to rapid onset of a life-threatening respiratory insufficiency (6). The development of acute lung injury (ALI) as well acute respiratory distress syndrome (ARDS) is common in those cases. Animal models for human ALI and ARDS are generated by systemic infusion of live bacteria or endotoxin of gram-negative bacteria (9). Cytokines, such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) have been identified as important pathogenic mediators of endotoxin-induced ALI (38). During sepsis, the alveolar compartmentalization is lost, allowing passage of cytokines, which eventually can be released into the bloodstream by other organs, and ultimately to the pulmonary endothelium. These cytokines, especially IL-1, TNF-α and IL-8, have important roles in lung

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Section: Animals and Treatmentsmentioning

confidence: 96%

Time-dependent expression of endothelin-1 in lungs and the effects of TNF-α blocking peptide on acute lung injury in an endotoxemic rat model

et al. 2011

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“…We found an early significant decrease in Edn1 lung expression following kidney IRI, and therefore found it to be an ideal candidate gene to validate our ability to accurately measure genes whose expression is deactivated following treatment. In addition, Edn-1 is a potent vasoconstrictor and its expression is associated with pulmonary endothelial injury and microvascular leak (15,21). The deactivation of gene expression at 6 h may represent a response to an increase in early protein abundance or activity, and given that it is also the gene with most links to "acute lung injury" term in the PubMed database, makes Edn1 an attractive candidate gene to be investigated as a potential mediator of AKI-induced ALI in future studies.…”

Section: Discussionmentioning

confidence: 99%

Ischemic acute kidney injury induces a distant organ functional and genomic response distinguishable from bilateral nephrectomy

Hassoun

Grigoryev²,

Lie

et al. 2007

American Journal of Physiology-Renal Physiology

184

168

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Hassoun HT, Grigoryev DN, Lie ML, Liu M, Cheadle C, Tuder RM, Rabb H. Ischemic acute kidney injury induces a distant organ functional and genomic response distinguishable from bilateral nephrectomy. Am J Physiol Renal Physiol 293: F30-F40, 2007. First published February 27, 2007 doi:10.1152/ajprenal.00023.2007.-Acute kidney injury (AKI) is associated with significant mortality, which increases further when combined with acute lung injury. Experiments in rodents have shown that kidney ischemia-reperfusion injury (IRI) facilitates lung injury and inflammation. To identify potential ischemia-specific lung molecular pathways involved, we conducted global gene expression profiling of lung 6 or 36 h following 1) bilateral kidney IRI, 2) bilateral nephrectomy (BNx), and 3) sham laparotomy in C57BL/6J mice. Bronchoalveolar lavage fluid analysis revealed increased total protein, and lung histology revealed increased cellular inflammation following IRI, but not BNx, compared with sham controls. Total RNA from whole lung was isolated and hybridized to 430MOEA (22,626 genes) GeneChips (n ϭ 3/group), which were analyzed by robust multichip average and significance analysis of microarrays and linked to gene ontology (GO) terms using MAPPFinder. The microarray power analysis predicted that the false discovery rate (q Ͻ 1%) and Ն50%-fold change compared with sham would represent significant changes in gene expression. Analysis identified 266 and 455 ischemia-specific, AKI-associated lung genes with increased expression and 615 and 204 with decreased expression at 6 and 36 h, respectively, compared with sham controls. Real-time PCR analysis validated select array changes in lung serum amyloid A3 and endothelin-1. GO analysis revealed significant activation (Z Ͼ 1.95) of several proinflammatory and proapoptotic biological processes. Ischemic AKI induces functional and transcriptional changes in the lung distinct from those induced by uremia alone. Further investigation using this lung molecular signature induced by kidney IRI will provide mechanistic insights and new therapies for critically ill patients with AKI.ischemia-reperfusion; lung injury; microarray ISCHEMIC ACUTE KIDNEY INJURY (AKI) occurs in various clinical settings including shock, sepsis, transplantation, and vascular surgery. Despite advances in renal replacement therapy, the mortality of patients with AKI has remained high over the past few decades, and renal insufficiency continues to be a sensitive marker for a poor outcome in critically ill patients (2, 22). Epidemiological studies have identified an association between AKI and dysfunction of extrarenal organs (4). Given the persistent AKI-associated poor clinical outcomes, there is a need to study the systemic and remote organ effects that occur in the context of AKI.Acute lung injury (ALI) is a significant cause of respiratory failure in the intensive care unit and carries a substantial mortality of 30 -40% (8). When combined with AKI, mortality approaches 80% (26). The clinical presentation of AKI-associate...

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“…Studies have shown that LPS stimulates the synthesis of ET-1 both in vivo and in vitro (Ohta et al 1990;Forni et al 2005;Zaedi et al 2006). Furthermore, the use of a nonselective endothelin receptor antagonist, tezosentan, has been shown to limit various hemodynamic abnormalities associated with endotoxemia, including pulmonary edema (Kuklin et al 2004;Rossi et al 2004).…”

Section: Discussionmentioning

confidence: 99%

Preferential recruitment of neutrophils by endothelin-1 in acute lung inflammation induced by lipopolysaccharide or cigarette smoke

Bhavsar

Liu²,

Patel³

et al. 2008

COPD

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This study examined the role of endothelin-1 (ET-1) in recruiting infl ammatory cells to the lung after induction of injury with either lipopolysaccharide (LPS) or cigarette smoke. Hamsters injected with either ET-1 or its precursor peptide (Big ET-1) prior to treatment with LPS or cigarette smoke had markedly increased concentrations of neutrophils in bronchoalveolar lavage fl uid (BALF) despite a reduction in total numbers of BALF leukocytes. Furthermore, the effect of ET-1 on smoke-exposed animals was reversed by addition of an endothelin-A receptor antagonist. These results are consistent with preferential recruitment of neutrophils by ET-1, and suggest that inhibition of this proinfl ammatory mediator may decrease acute pulmonary infl ammation associated with cigarette smoke and other pulmonary toxins.

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Novel endothelin receptor antagonist attenuates endotoxin-induced lung injury in sheep

Abstract: In an ovine model of endotoxin-induced lung injury, tezosentan ameliorates pulmonary hypertension, lung edema, cardiac dysfunction, and arterial hypoxemia. Tezosentan counteracts the hemodynamic effects of endothelin-1 in a dose-dependent manner.

Cited by 46 publications

References 34 publications

Time-dependent expression of endothelin-1 in lungs and the effects of TNF-α blocking peptide on acute lung injury in an endotoxemic rat model

Time-dependent expression of endothelin-1 in lungs and the effects of TNF-α blocking peptide on acute lung injury in an endotoxemic rat model

Ischemic acute kidney injury induces a distant organ functional and genomic response distinguishable from bilateral nephrectomy

Preferential recruitment of neutrophils by endothelin-1 in acute lung inflammation induced by lipopolysaccharide or cigarette smoke

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